This invention relates to a process for preparing 13-alkyl-17.alpha.-substituted- 17.beta.-acyloxy-4-en-3-one steroids, wherein the 17.alpha.-substituent may be an alkyl, alkenyl, or alkynyl group. The 17.beta.-hydroxy-precursors of these esters are well-known and in a totally synthetic process are prepared by hydrolysis of suitably substituted 3-alkoxy-2,5(10)-gonadienes (see for example U.K. Pat. Nos. 1,041,279 and 1,111,449). The 13-alkyl-17.alpha.-substituted-17.beta.-acyloxy-4-en-3-one steroids are well-known for their pharmaceutical efficacy; thus, for example, norethindrone acetate is currently being marketed as an orally active progestational agent. A process for their synthesis which requires several steps is described in U.K. Pat. No. 1,113,813.
In this particular process 13.beta.-ethyl-17.alpha.-ethynylgon-4-en-17.beta.-ol-3-one is contacted with an acylating agent such as acetic anhydride producing 3,17.beta.-diacetoxy-13.beta.-ethyl-17.alpha.-ethynyl-3,5-diene. This diacylated material must next be selectively deacylated at the 3-position to produce the desired 17.beta.-acetoxy-13.beta.-ethyl-17.alpha.-ethynylgon-4-en-3-one. It can be seen that in this process the conditions necessary for the acylation of the 17.beta.-hydroxy group of the 17.beta.-hydroxygon-4-en-3-one are also sufficient to form the 3-enol acylate, which ester must be subsequently hydrolyzed by a carefully controlled preferential deacylation at the 3-position in order to produce the desired 17.beta.-acetoxygon-4-en-3-one (see for example U.S. Pat. No. 2,964,537 and U.K. Pat. No. 1,113,813). It is also known, that the acylation reaction itself, must be carefully controlled in order to prevent dehydration of the tertiary alcohol function at the 17-position.
Alternatively, the ketone function of a 17.beta.-hydroxygon-4-en-3-one must be protected by any of the ordinary ketone-protecting groups (e.g. ethylene ketal) prior to the acylation of the 17-alcohol function. The ketone-protecting group must, however, be removed in a subsequent procedure in order to produce the desired 17.beta.-acyloxygon-4-en-3-one. Thus, prior to the discovery of the instant invention the methods available to mono-acylate a 17.beta.-hydroxygon-4-en-3-one required several steps, each of which possibly being accompanied by unwanted side reactions.
An additional advantage of the instant process is that the starting materials are 13-alkyl-17.alpha.-substituted-3-alkoxygona-2,5(10)-dien-17.beta.-ols, and not the gon-4-en-3-ones derived from them. Those skilled in the art will appreciate the economies inuring to the elimination of each additional step in a synthetic process.
The new and practical process of the present invention thus provides a means whereby a 17.beta.-acyloxy-13.beta.-alkyl-17.alpha.-substituted-gon-4-en-3-one may be prepared directly from the correspondingly substituted 3-alkoxygona-2,5(10)-dien-17.beta.-ol in an efficient one-step reaction process.